With recent developments in the field of oncology and cell biology, researchers have been able to begin drug development programs that specifically target the underlying cause of cancer, particularly if the cause is the deficiency or mutation of specific gene products. Therefore, if clinicians have the tools to determine the cause of cancer for each cancer patient, a treatment regime can be chosen which is tailored for the specific cause with optimized efficacy.
The ras oncogene accounts for a large number of tumors. Activating mutations of the ras gene itself occur in about 30% of all human tumors (Bos, J. L., 1989), primarily in pancreatic (90%), sporadic colorectal (50%) and lung (40%) carcinomas, as well as myeloid leukemia (30%). In addition to mutations of the ras gene itself, activation of the factors upstream or downstream of ras in the ras pathway is also associated with tumors. For example, overexpression of HER2/Neu/ErbB2 or the epidermal growth factor (EGF) receptor is common in breast cancer (25-30%), and overexpression of platelet-derived growth factor (PDGF) receptor or EGF receptor is prevalent in gliomas and glioblastomas (40-50%). EGF receptor and PDGF receptor are both known to activate ras upon binding to their respective ligand, and v-erbB encodes a constitutively activated receptor lacking the extracellular domain. Altogether, direct mutation of the ras oncogene or an upstream element in the ras pathway is believed to occur in approximately two thirds of all tumors.
Given the significant role of the ras pathway in tumorigenesis, it is desirable to be able to determine if a tumor is associated with activation of the ras pathway so that a specifically tailored treatment regime may be developed. Prior to the present invention, however, there has not been a simple and sensitive method of diagnosing the association of a cancer with the ras pathway. While mutations in the ras structural gene may be detected with a high sensitivity by polymerase chain reaction (PCR), there are many other factors in the ras pathway which may be the cause of high ras activity, such as mutations in the ras gene flanking sequences which lead to abnormally high expression level of the ras gene product, mutations in the structural genes of a factor upstream or downstream of ras in the ras pathway, or regulatory mutations which affect the expression levels of these upstream or downstream factors. Therefore, PCR for the ras gene does not precisely identify all cancers associated with activation of the ras pathway. The need remains for a simple and precise method of diagnosing ras-activated tumors.